Chronic Suppression of Periprosthetic Joint Infections ...jc.dalortho.ca/wp-content/uploads/2015/10/chronic-antibiotic-su... · Chronic Suppression of Periprosthetic Joint Infections

Chronic Suppression of Periprosthetic JointInfections with Oral Antibiotics Increases

Infection-Free SurvivorshipMarcelo B.P. Siqueira, MD, Anas Saleh, MD, Alison K. Klika, MS, Colin O’Rourke, MS,

Steven Schmitt, MD, Carlos A. Higuera, MD, and Wael K. Barsoum, MD

Investigation performed at the Orthopaedic and Rheumatologic Institute, Cleveland Clinic Foundation, Cleveland, Ohio

Background: The clinical benefit of chronic suppression with oral antibiotics as a salvage treatment for periprostheticjoint infection is unclear. The purpose of this study was to compare infection-free prosthetic survival rates between pa-tients who received chronic oral antibiotics and those who did not following irrigation and debridement with polyethyleneexchange or two-stage revision for periprosthetic joint infection.

Methods: We reviewed the records on all irrigation and debridement procedures with polyethylene exchange and two-stage revisions performed at our institution from 1996 to 2010 for hip or knee periprosthetic joint infection. Of 625patients treated with a total of 655 eligible revisions, ninety-two received chronic oral antibiotics for a minimum of sixmonths and were eligible for inclusion in our study. These patients were compared with a matched cohort (ratio of 1:3)who did not receive chronic oral antibiotics.

Results: The five-year infection-free prosthetic survival rate was 68.5% (95% confidence interval [CI] = 59.2% to 79.3%)for the antibiotic-suppression group and 41.1% (95% CI = 34.9% to 48.5%) for the non-suppression group (hazard ratio[HR] = 0.63, p = 0.008). Stratification by the type of surgery and the infecting organism showed a higher five-year survivalrate for the patients in the suppression group who underwent irrigation and debridement with polyethylene exchange(64.7%) compared with those in the non-suppression group who underwent irrigation and debridement with polyethyleneexchange (30.4%, p < 0.0001) and a higher five-year survival rate for the patients in the suppression group who had aStaphylococcus aureus infection (57.4%) compared with those in the non-suppression group who had a Staphylococcusaureus infection (40.1%, p = 0.047).

Conclusions: Chronic suppression with oral antibiotics increased the infection-free prosthetic survival rate followingsurgical treatment for periprosthetic joint infection. Patients who underwent irrigation and debridement with polyethyleneexchange and those who had a Staphylococcus aureus infection had the greatest benefit.

Level of Evidence: Therapeutic Level III. See the Instructions for Authors for a complete description of levels of evidence.

Periprosthetic joint infection is a devastating complicationof total knee and hip arthroplasty that is associated withsubstantial morbidity1,2, mortality 3, and economic bur-

den4,5. The risk of infection following total joint arthroplasty is

approximately 1%4,6,7. Treatment guidelines for periprosthetic jointinfection recommend irrigation and debridement with polyeth-ylene exchange for acute infections caused by low-virulencepathogens around well-fixed implants and two-stage revision

Disclosure: None of the authors received payments or services, either directly or indirectly (i.e., via his or her institution), from a third party in support ofany aspect of this work. One or more of the authors, or his or her institution, has had a financial relationship, in the thirty-six months prior to submission ofthis work, with an entity in the biomedical arena that could be perceived to influence or have the potential to influence what is written in this work. Noauthor has had any other relationships, or has engaged in any other activities, that could be perceived to influence or have the potential to influence whatis written in this work. The complete Disclosures of Potential Conflicts of Interest submitted by authors are always provided with the online version ofthe article.

Peer Review: This article was reviewed by the Editor-in-Chief and one Deputy Editor, and it underwent blinded review by two or more outside experts. It was also reviewedby an expert in methodology and statistics. The Deputy Editor reviewed each revision of the article, and it underwent a final review by the Editor-in-Chief prior to publication.Final corrections and clarifications occurred during one or more exchanges between the author(s) and copyeditors.

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COPYRIGHT � 2015 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED

J Bone Joint Surg Am. 2015;97:1220-32 d http://dx.doi.org/10.2106/JBJS.N.00999

for infections that are chronic, caused by a high-virulence path-ogen, or around a loose component8. A two to six-week postop-erative course of pathogen-specific intravenous antibiotic therapyis also recommended in both cases9. Despite optimal surgical andmedical treatments, failure rates are still high, with five-yearprosthetic survival rates ranging from 38.4%10 to 64.7%11.

Chronic antibiotic suppression is an unproven methodthat has been used in an attempt to increase the chance of re-taining a functional prosthesis in certain patients, typically thosewho have undergone surgical treatment for periprosthetic jointinfection but have a high risk of relapse and/or for whom the nextsurgical step would be limb-threatening. There are no clearlydefined criteria for increased risk of relapse, although commonfactors include a history of multiple joint infections, immuno-suppression, comorbidities that predispose to periprosthetic jointinfection, and a virulent pathogen9,12. Candidates for chronicantibiotic suppression must also have the ability to tolerate side-effects.

The purpose of this study was to evaluate patients whounderwent irrigation and debridement with polyethylene ex-change or two-stage revision in order to (1) compare infection-free prosthetic survivorship between patients who did and thosewho did not undergo subsequent chronic oral antibiotic sup-pression; (2) analyze infection-free survivorship stratified by thetype of surgery, infecting organism, and involved joint; and (3)determine factors associated with failure of chronic suppressionwith oral antibiotics and build a nomogram to preoperativelypredict the probability of failure.

Materials and Methods

After institutional review board approval was obtained, we used a combina-tion of Current Procedural Terminology (CPT)-4 and International Clas-

sification of Diseases, Ninth Revision (ICD-9) codes to identify all revision totalknee and hip arthroplasties performed from 1996 to 2010 at a single institution.Of 10,411 procedures that were identified, 7111 that were done for indicationsother than periprosthetic joint infection, 2510 that were not either an irrigationand debridement with polyethylene exchange or a complete two-stage revision,

TABLE I Results of Univariate Analyses Comparing Baseline Characteristics Between Suppression and Non-Suppression Groups

Variable Suppression Group (N = 92) Non-Suppression Group (N = 276) P Value

Charlson comorbidity index* 4 [3, 5] 4 [2, 5] 0.34

Age† (yr) 63.7 ± 11.7 64.2 ± 11.5 0.72

BMI† (kg/m2) 33.6 ± 9.2 33.2 ± 8.6 0.71

Sex‡ 0.90

Female 36 (39.1) 112 (40.6)

Male 56 (60.9) 164 (59.4)

Index surgery‡ 0.63

Irrigation and debridement with polyethyleneexchange

54 (58.7) 152 (55.1)

2-stage revision 38 (41.3) 124 (44.9)

No. of previous revisions* 1 [0, 3] 1 [0, 2] 0.37

Pathogen‡ 0.33

S. aureus 44 (47.8) 114 (41.3)

Non-S. aureus 48 (52.2) 162 (58.7)

Joint‡ 0.94

Knee 71 (77.2) 210 (76.1)

Hip 21 (22.8) 66 (23.9)

Duration of symptoms* (days) 30 [7, 90] 14 [5, 45] 0.024

Duration of intravenous antibiotic therapy* (wk) 6 [6, 6] 6 [6, 6] 0.17

Previous joint infection anywhere‡ 41 (44.6) 130 (47.1) 0.76

Infecting organism class‡ 0.21

Virulent§ 54 (58.7) 147 (53.2)

Indolent# 31 (33.7) 55 (20.0)

Fungal and acid-fast bacilli 0 1 (0.3)

Miscellaneous and contaminants 5 (5.4) 22 (7.2)

Multiple organisms‡ 18 (19.6) 35 (12.7) 0.13

*The values are given as the median with the 25th and 75th percentiles in brackets. †The values are given as the mean and standard deviation.‡The values are given as the number of patients with the percentage in parentheses. §Includes S. aureus, Enterococcus, and gram-negativeorganisms. #Includes coagulase-negative Staphylococcus and Propionibacterium species.

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THE JOURNAL OF BONE & JOINT SURGERY d J B J S .ORG

VOLUME 97-A d NUMBER 15 d AUGUST 5, 2015CHRONIC SUPPRESS ION OF PER IPROSTHET IC JO INT INFECT IONS

WITH ORAL ANTIB IOT ICS

and 135 that were done for a condition that did not fulfill the criteria for peri-prosthetic joint infection

12were excluded. This left 655 eligible procedures in

625 patients for the study (Fig. 1).Of the 655 procedures, 379 were two-stage revisions (240 knees and 139

hips) and 276 were irrigation and debridement procedures with polyethyleneexchange (207 knees and sixty-nine hips). Chart review and obituary databasesearches were performed. All cases were comanaged with the infectious diseasesservice at our hospital. Patients received broad-spectrum intravenous antibioticsfollowing the first stage of the two-stage revision or following irrigation anddebridement with polyethylene exchange. An organism-specific antibiotic regi-men was started after culture results were obtained. One hundred and twentypatients received chronic antibiotic suppression, defined as treatment with oralantibiotics for a minimum of six months following the initial course of intra-venous antibiotics. As we are aware of no current specific indication for chronicantibiotic suppression, the decision of whether to offer this treatment was in-dividualized. Patients with intraoperative cultures that were positive for virulentpathogens received antibiotic suppression if they had a risk factor for reinfection(a history of multiple joint infections, previous failed surgery for periprostheticjoint infection, retained implants and/or immunosuppression). Patients with lessvirulent pathogens or negative cultures received antibiotic suppression if theyhad multiple risk factors for reinfection. The patients were contacted by telephoneand questioned regarding compliance with the antibiotic therapy, additional jointsurgery, joint pain, and drainage. Outcomes and death rates were recorded.Exclusion criteria included non-compliance (n = 9), less than one year of follow-up (n = 12), and initiation of oral antibiotic therapy after the onset of newdrainage (n = 7). This resulted in ninety-two patients eligible for the study.

The non-suppression group was selected from the remaining pool of 505patients in whom a total of 535 periprosthetic joint infections had been managedwithout chronic antibiotic suppression. In an effort tomanage the inherent selectionbias, the suppression-group patients were matched with similar, non-suppression-group patients. Propensity score matching was used for age, sex, body mass index(BMI), Charlson comorbidity index, number of previous operations on the affectedjoint, affected joint (hip or knee), type of surgery (irrigation and debridement withpolyethylene exchange versus two-stage revision) preceding the antibiotic suppres-sion, and infecting organism (Staphylococcus aureus versus non-S. aureus).Althoughthe Charlson comorbidity index was developed to predict mortality within one yearafter hospital admission

13,14, it has been shown to be an independent predictor of

periprosthetic joint infection in both the hip15and the knee

16. Propensity scores

were estimated on the scale of the log-odds based on the above variables with use ofa logistic regressionmodel. Patients in the suppression group were matched to thosein the non-suppression groupwith the closest propensity scoreswithout replacementin a ratio of 1:3 (suppression:non-suppression). The covariate balance resultingfrom propensity score matching was checked with use of standardized differences,variance ratios of propensity scores, and variance ratios of residuals orthogonalto propensity scores for each covariate. Balance was found to be adequate withoutrestricting which patients were matched by enforcing a matching caliper.

The primary outcome variable was infection-free prosthetic survival,with additional surgery due to infection or death as the end points. All patientswere included in the analysis even if the time to the outcome was less than oneyear. Further stratification on the basis of the affected joint, type of index surgery,and infecting organism was performed. Treatment failure was the outcomevariable used to compare the patients in the suppression group for whom the

Fig. 1

Flowchart showing eligible cases of chronic antibiotic suppression and matched cases without suppression. I&D = irrigation and debridement,

PJI = periprosthetic joint infection, SA = S. aureus, and C.I. = comorbidity index.

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TABLE II Intravenous and Oral Antibiotic Regimens for the Suppression Group According to Pathogen*

Pathogen (No. of Patients)IV Antibiotic Regimen [Adjunctive PO Antibiotic

Regimen] (No. of Patients)Chronic Suppressive Antibiotic Regimen

(No. of Patients)

Methicillin-sensitiveStaphylococcus aureus (31)

Oxacillin 2 g qid or q4h (14)

Vancomycin 1 or 1.5 or 2 g bid or qd or q48h (8)

Cefazolin 1 or 2 g tid (4)

Imipenem 500 mg qid (1)

Daptomycin 500 mg qd (1)

Ceftriaxone 2 g qd (1)

Ampicillin/sulbactam 2/1 g qid (1)

Clindamycin 900 mg tid (1)

Piperacillin/tazobactam 3/0.375 g tid (1)

Dicloxacillin 500 mg qid or tid or bid (11)

Doxycycline 100 mg qid or bid or qd (7)

Cephalexin 500 mg qid or tid or bid (6)

Trimethoprim/sulfamethoxazole 160/800 mg bid (5)

Minocycline 100 mg qd (1)

Amoxicillin 500 mg tid (1)

Clindamycin 300 mg bid (1)

Methicillin-resistantcoagulase-negativestaphylococci (21)

Vancomycin 1 or 1.25 or 1.5 g bid or qd (14)

Daptomycin 500 or 650 mg qd (3)

Oxacillin 2 g qid (1)


Linezolid 600 mg bid (1)

Tigecycline 50 mg bid (1)

Doxycycline 100 mg bid or qd (12)

Rifampin 300 mg bid (2)

Trimethoprim/sulfamethoxazole 160/800 mgbid or qd (4)


Dicloxacillin 500 mg qid (2)

Cephalexin 250 mg bid (1)

Methicillin-resistantStaphylococcus aureus (13)


Daptomycin 350 or 500 mg qd (2)

Oxacillin 2 g qid (1)


Doxycycline 100 mg bid (1)

Doxycycline 100 mg qd (8)



Erythromycin 400 mg bid (1)

Methicillin-sensitivecoagulase-negativestaphylococci (12)


Oxacillin 1 or 2 g q4h or qid (2)





Dicloxacillin 250 or 500 mg tid (3)

Cephalexin 500 mg tid (1)

Cefadroxil 500 mg bid (1)

Enterococci (5) Ampicillin 2 g q4h (2)

Penicillin 1 million U qid (1)

Tigecycline 50 mg bid (1)

Vancomycin 1 g qd (1)



Ciprofloxacin 500 mg bid (1)

Viridans streptococci (5) Ceftriaxone 2 g qd (2)

Piperacillin/tazobactam 3/0.375 g qid (1)


Cefazolin 1 g tid (1)



Moxifloxacin 400 mg qd (1)


Group-B streptococci (3) Penicillin G 2 million U q4h (1)

Ampicillin 2 g qid (1)

Vancomycin 1 g bid (1)


Dicloxacillin 250 mg tid (1)

Diphtheroid-like bacilli (2) Vancomycin 1 g bid [ciprofloxacin 500 mg bid (1)or rifampin 300 mg PO bid (1)] (2)


Enterobacteriaceae (2) Imipenem 500 mg qid [ciprofloxacin 750 mg bid] (1)



Propionibacterium acnes (2) Vancomycin 1 or 1.5 g bid or qd (2) Doxycycline 100 mg bid or qd (2)

Pseudomonas aeruginosa (1) Imipenem 500 mg qid [ciprofloxacin 750 mg bid] (1) Ciprofloxacin 500 mg bid (1)

Staphylococcus lugdunensis (1) Oxacillin 2 g q4h [rifampin 300 mg bid] (1) Cephalexin 500 mg tid (1)

Ureaplasma species (1) Ceftazidime 2 g qd (1) Azithromycin 500 mg qd (1)

Negative culture (1) Vancomycin 1 g bid (1) Doxycycline 100 mg bid (1)

*IV = intravenously, PO = orally, qid = four times a day, q4h = every four hours, tid = three times a day, bid = twice a day, qd = every day, and q48h = every forty-eight hours. The number of pathogens adds up to more than the total number of ninety-two patients because some patients had polymicrobial infections. Also,the number of antibiotic regimens may add up to more than the total number of pathogens because some patients had multiple regimens at once.

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TABLE III Intravenous Antibiotic Regimens for the Non-Suppression Group According to Pathogen*

Pathogen (No. of Patients) IV Antibiotic Regimen [Adjunctive PO Antibiotic Regimen] (No. of Patients)

Methicillin-sensitive Staphylococcusaureus (61)

Oxacillin 2 g q4h or qid [rifampin 300 mg bid (9)] (25)

Vancomycin 500 mg or 1 or 1.25 g bid or qd [rifampin 300 or 600 mg bid (2)] (16)

Cefazolin 1 or 2 g bid or tid (9)

Penicillin G 3 million U q4h [rifampin 300 mg bid (1)] (3)




Amoxicillin 1 g tid (1)



Ampicillin/sulbactam 2/1 g qid (1)


Methicillin-resistant Staphylococcusaureus (53)

Vancomycin 500 mg or 1 or 1.25 or 1.5 g bid or qd or q48h or q72h[rifampin 300 mg bid (14)] (45)


Piperacillin 4 g tid (1)


Oxacillin 2 g q4h (1)




Methicillin-sensitive coagulase-negativestaphylococci (34)

Vancomycin 1 or 1.25 or 1.5 g bid or qd or q48h [rifampin 300 mg bid (4)] (29)

Cefazolin 1 or 2 g tid (2)



Piperacillin/tazobactam 3/0.375 g qid (1)

Methicillin-resistant coagulase-negativestaphylococci (29)

Vancomycin 750 mg or 1 or 1.25 or 1.5 g bid or qd [rifampin 300 or 600 mg bid (2)] (24)



Aztreonam 1 g q8h (1)

Diphtheroid-like bacilli (9) Vancomycin 750 mg or 1 or 1.5 g bid or qd or q48h [ciprofloxacin 750 mg bid (6)] (8)

Gentamycin 50 mg qd (1)

[Ciprofloxacin 500 mg bid (1)]

[Azithromycin 500 mg qd (1)]

Enterococci (8) Vancomycin 1.5 g bid (4)


Piperacillin/tazobactam 3/0.375 g qid [ciprofloxacin 750 mg bid (1)] (2)

Pseudomonas aeruginosa (8) Piperacillin/tazobactam 3/0.375 g qid or tid or bid [ciprofloxacin 500 mg bid (1)] (7)

Daptomycin 570 mg qd [ciprofloxacin 500 mg bid] (1)

Viridans streptococci (6) Penicillin G 3 million U q4h (2)

Vancomycin 1 g bid or qd (2)



Group-B streptococci (6) Vancomycin 1 g bid [rifampin 300 mg bid (1)] (2)



Penicillin G 3 million U tid (1)

continued

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TABLE III (continued)

Pathogen (No. of Patients) IV Antibiotic Regimen [Adjunctive PO Antibiotic Regimen] (No. of Patients)

Escherichia coli (5) Vancomycin 1 g bid [ciprofloxacin 500 mg bid (2)] (2)

Ertapenem 1 g qd [metronidazole 250 mg tid] (1)

[Levofloxacin 750 mg qd (1)]

[Ciprofloxacin 500 mg bid (1)]

Unspecified b-hemolytic streptococci (5) Vancomycin 1 or 1.5 g qd (3)


Penicillin G 4 million U tid (1)

Klebsiella pneumoniae (4) Tigecycline 50 mg bid (2)


Daptomycin 570 mg qd [ciprofloxacin 500 mg bid] (1)

Propionibacterium acnes (3) Vancomycin 1 g qd (2)

Ampicillin 2 g tid (1)

Serratia marcescens (3) Vancomycin 1 g bid [ciprofloxacin 750 mg bid (1)] (3)

Gentamycin 50 mg qd (2)

Peptostreptococcus species (3) Oxacillin 2 g qid [rifampin 300 mg bid] (1)

Vancomycin 1.25 g bid (1)

Cefazolin 2 g bid (1)

Streptococcus pneumoniae (2) Vancomycin 1.25 g bid (1)


Group-C streptococci (2) Vancomycin 1 g bid (2)

Group-A streptococci (1) Vancomycin 1 g bid (1)

Group-G streptococci (1) Ampicillin 2 g qid (1)

Enterobacteriaceae (1) Ceftriaxone 1 g qd (1)

Bacteroides fragilis (1) Metronidazole 250 mg tid (1)

Candida parapsilosis (1) [Fluconazole 400 mg qd (1)]

Proteus mirabilis (1) Ceftazidime 1 g qd (1)

Morganella morganii (1) Ciprofloxacin 400 mg qd (1)

Staphylococcus lugdunensis (1) Oxacillin 2 g q4h [rifampin 600 mg qd] (1)

Negative culture (32) Vancomycin 1 or 1.5 g bid or qd or q48h [rifampin300 mg bid (1) or ciprofloxacin 500 mg bid (1)] (12)


Oxacillin 2 g q4h [rifampin 300 mg bid (1)] (2)


Vancomycin 1 g bid [ciprofloxacin 500 mg bid] (1)


Ticarcillin/clavulanate 3/0.1 g qd (1)

Ciprofloxacin 400 mg qd (1)


Penicillin G 4 million U q4h (1)



[Levofloxacin 500 mg qd (1)]

*IV = intravenously, PO = orally, q4h = every four hours, qid = four times a day, bid = twice a day, qd = every day, tid = three times a day, q48h = everyforty-eight hours, q72h = every seventy-two hours, and q8h = every eight hours. The number of pathogens adds up to more than the total number of276patients becausesomepatients hadpolymicrobial infections. Also, the number of antibiotic regimensmayaddup tomore than the total numberof pathogens because some patients had multiple regimens at once.

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suppression failed with those for whom it did not fail. Failure was defined, asdescribed by Diaz-Ledezma et al.

17, as (1) subsequent surgical intervention for

infection after the index procedure; (2) persistent fistula, drainage, or joint painat the last follow-up visit; or (3) death related to the periprosthetic joint infection.Any unresolved drainage at the last follow-up visit was considered a failure. Painwas considered to indicate a failure only when it was severely debilitating andprevented any kind of walking at the time of the last follow-up. Because we couldnot determine the causes of most deaths, we considered death within one yearafter the surgery as the cutoff point for failure; this was based on the findings ofZmistowski et al.

3, who showed that the highest differential mortality between

septic and aseptic revisions occurred within one year.The Fisher exact test or Pearson chi-square test was used for categorical data,

whereas the Wilcoxon rank sum test or Welch two-sample t test was used for con-tinuous data. Infection-free survival was estimated by using the Kaplan-Meiermethod. Hazard ratios (HRs) for comparison between the suppression and non-suppression groups were calculated with use of Cox proportional hazards regressionmodels, with adjustment for variables that were previously used for matching. Subsetanalyses were performed by selecting the matched groups in which all subjects be-longed to the subset of interest. This was done to preserve the matching charac-teristics of the original data, and the propensity score balance was rechecked withinthese subsets to verify that this had been accomplished. A log-rank test was used tocompare prosthetic survival between the suppression and non-suppression groups inthe subset cohorts. Further modeling was performed with Cox proportional hazardsmodels to verify the effect of chronic antibiotic therapy across the different subsets.This model compared the benefits of suppression between the subsets of infectingorganism (methicillin-resistant S. aureus [MRSA] versus methicillin-sensitive S. aureus[MSSA] versus non-S. aureus), affected joint (hip versus knee), and type of surgery(irrigation and debridement with polyethylene exchange versus two-stage revision).

Failures within the suppression group were modeled as a function ofclinically relevant variables, with use of a penalized logistic regression model

18. As a

result of a low ratio of events to parameters, thismodel included only three variablesand used a ridge-type penalty to correct for possible overfitting. A significance levelof 5% was used, and analyses were done with use of R software (version 3.0.2; RFoundation for Statistical Computing, Vienna, Austria). The penalized model wasfit with use of rms (regression modeling strategies) in the R package

19.

Source of FundingThis study was internally funded by our institution.

Results

The baseline characteristics of the suppression and non-suppression groups are depicted in Table I.The mean duration of follow-up (and standard deviation)

was 69.1 ± 38.2 months (range, 2.2 to 168.3 months) in the sup-pression group and 41.6 ± 40.2 months (range, less than one to183 months in the non-suppression group). Sixty-two (67.4%)

of the patients in the suppression group and 186 (67.4%) of thosein the non-suppression group had had previous revisions (mean,2.7 ± 1.4 and 2.4 ± 1.7 previous revisions, respectively) for anycause. With the exception of two knees and one hip (all in thenon-suppression group), which had a resection arthroplasty, allknees were treated with static spacers and all hips were treatedwith articulated spacers at the time of explantation. The timeinterval between removal and reimplantation was variable, av-eraging 21.1 ± 9.7 weeks (range, 6.6 to 46.3 weeks) in the sup-pression group and 15 ± 8 weeks (range, 3.1 to 45.6 weeks) in thenon-suppression group. The median duration of postoperativeintravenous therapy with antibiotics was six weeks in bothgroups. The mean duration of oral antibiotic suppression was63.5 ± 38.3 months (range, six to 165.1 months). The specificantibiotic regimens are depicted in Tables II and III.

The five-year infection-free prosthetic survival rate was68.5% (95% confidence interval [CI] = 59.2% to 79.3%) for theantibiotic-suppression group compared with 41.1 % (95% CI =34.9% to 48.5%) for the non-suppression group (HR = 0.63, p=0.008) (Fig. 2). The Cox proportional hazards model showed

TABLE IV Cox Proportional Hazards Model Estimates of Survival, with Adjustment for Matching Covariates

Variable HR 95% CI P Value

Chronic suppressive antibiotics 0.48 0.34-0.67 <0.001

No. of previous revisions 1.12 1.04-1.21 0.005

Non-S. aureus infection 0.69 0.51-0.94 0.018

Age (per year) 1.01 1.00-1.03 0.11

Hip joint 0.86 0.59-1.24 0.42

Charlson comorbidity index (per index point) 1.02 0.92-1.14 0.67

Male sex 1.05 0.78-1.40 0.76

BMI (per index point) 1.00 0.99-1.02 0.92

Fig. 2

Kaplan-Meier infection-free prosthetic survival curves for suppression

and non-suppression patient groups. The blue line represents the sup-

pression group, and the red line represents the non-suppression group; the

shaded areas surrounding the lines represent the 95% CI.

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that a higher number of previous revisions predicted a decreasedsurvival rate (HR = 1.12 [95%CI = 1.04 to 1.21]; p = 0.005) anda non-S. aureus infection predicted an increased survival rate(HR = 0.69 [95% CI = 0.51 to 0.94]; p = 0.018) (Table IV).

Stratification by the type of index surgery showed that, in thegroup that underwent irrigation and debridement with poly-

ethylene exchange, the patients treated with chronic antibiotic sup-pression had an increased five-year infection-free survival rate (64.7%[95% CI = 49.7% to 77.3%]) compared with the non-suppressiongroup (30.4% [95% CI = 22.4% to 39.6%]; p < 0.0001). There wasno difference in survival between the suppression and non-suppression groups following two-stage revision (p= 0.14) (Fig. 3).

TABLE V Comparisons of the Effects of Suppression Across Groups Stratified by Infecting Organism, Affected Joint, and Type of Surgery

Subset Interaction HR 95% CI

Methicillin-sensitive S. aureus vs. non-S. aureus 0.83 0.3-2.27

Methicillin-resistant S. aureus vs. non-S. aureus 0.42 0.11-1.63

Methicillin-resistant vs. methicillin-sensitive S. aureus 0.50 0.12-2.08

Hip vs. knee 0.33 0.09-1.2

Irrigation and debridement with polyethylene exchange vs. 2-stage revision 1.40 0.55-3.57

Fig. 3

Kaplan-Meier infection-free prosthetic survival curves for subset cohorts. The blue line represents the suppression group, and the red line represents

the non-suppression group; the shaded areas surrounding the lines represent the 95% CI. Fig. 3-A Individuals who underwent irrigation and debride-

ment with polyethylene exchange (p < 0.0001 for the difference between the suppression and non-suppression groups). Fig. 3-B Individuals who

underwent a two-stage revision (p = 0.14). Fig. 3-C Individuals with an S. aureus infection (p = 0.047). Fig. 3-D Individuals with a non-S. aureus infection

(p = 0.62). Fig. 3-E Individuals with an infection in the hip (p = 0.001). Fig. 3-F Individuals with an infection in the knee (p = 0.01).

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Stratification by the affected joint showed a significantincrease in the infection-free survival rate in the suppressiongroup, compared with the non-suppression group, both afterrevision for a hip infection (87.2% [95% CI = 60.2% to 96.8%]compared with 49.0% [95% CI = 32.9% to 65.4%]; p = 0.001)and after revision for a knee infection (65.8% [95%CI = 53.0%

to 76.7%] compared with 43.2% [95% CI = 35.4% to 51.4%];p = 0.01).

Stratification by the infecting organism showed that, whenthe pathogen was S. aureus, the five-year infection-free survivalrate in the suppression group (57.4% [95%CI= 39.2% to 73.8%])was increased compared with that in the non-suppression group

TABLE VI Results of Univariate Analyses Comparing Baseline Characteristics Between Patients for Whom Chronic Oral AntibioticSuppression Did Not Fail and Those for Whom It Failed

Variable No Failure (N = 60) Failure (N = 32) P Value

Age at revision* (yr) 64.92 ± 12.5 61.34 ± 9.81 0.13

Sex†

Male 34 (56.7) 22 (68.8)

Female 26 (43.3) 10 (31.3)

BMI* (kg/m2) 32.37 ± 9.01 35.83 ± 9.25 0.09

Index surgery† >0.99

Irrigation and debridement with polyethylene exchange 35 (58.3) 19 (59.4)

2-stage revision 25 (41.7) 13 (40.6)

Duration of intravenous antibiotic therapy‡ (wk) 6 [6, 6] 6 [6, 6] 0.26

Duration of symptoms‡ (days) 30 [6, 77.5] 28 [13.25, 83.75] 0.23

Onset of infection† 0.70

Early 24 (40.0) 12 (37.5)

Late 36 (60.0) 20 (62.5)

Joint† 0.012

Knee 41 (68.3) 30 (93.8)

Hip 19 (31.7) 2 (6.3)

No. of previous revisions* 1.47 ± 1.55 2.41 ± 1.9 0.02

Infecting organism class† 0.76

Virulent§ 35 (58.3) 19 (59.4)

Indolent# 19 (31.7) 12 (37.5)

Fungal and acid-fast bacilli 0 0

Miscellaneous and contaminants 4 (6.7) 1 (3.1)

Multiple organisms† 10 (16.7) 9 (28.8) 0.27

Pathogen† 0.93

S. aureus 28 (46.7) 16 (50.0)

Non-S. aureus 32 (53.3) 16 (50.0)

Duration of antibiotic suppression* (mo) 65.31 ± 37.01 59.87 ± 41.26 0.53

Charlson comorbidity index* 4.00 ± 1.48 3.66 ± 1.64 0.33

American Society of Anesthesiologists score‡ 3 [3, 3] 3 [2.75, 3] 0.89

Smoker† 4 (6.7) 3 (9.4) 0.69

Diabetes† 15 (25.0) 11 (34.4) 0.48

Inflammatory arthropathy† 10 (16.7) 1 (3.1) 0.089

Malignancy† 7 (11.7) 2 (6.3) 0.49

Steroid use† 9 (15.0) 2 (6.3) 0.32

Heart disease† 47 (78.3) 24 (75.0) 0.92

*The values are given as the mean and standard deviation. †The values are given as the number of patients with the percentage in parentheses.‡The values are given as the median with the 25th and 75th percentiles in brackets. §Includes S. aureus, Enterococcus, and gram-negativeorganisms. #Includes coagulase-negative Staphylococcus and Propionibacterium species.

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(40.1% [95% CI = 29.6% to 51.6%]; p = 0.047). There wasno difference in survival between the suppression and non-suppression groups when the patients had a non-S. aureusinfection (p = 0.62). The results of additional stratification, bywhether the patient had MRSA, MSSA, or gram-negative in-fection, are shown in Figure 4, although this analysis did notpreserve the original matching quality between the suppressionand non-suppression groups.

The benefit of chronic antibiotic suppression comparedacross different subsets was non-significant for the entire model(p = 0.22) and at every interaction (Table V).

Thirty-two patients (34.8%) in the suppression group and115 (41.7%) in the non-suppression group met the criteria forfailure of treatment. Comparisons between the patients forwhom chronic antibiotic suppression failed and those for whomit did not fail are depicted in Table VI. Failures had a lowerassociation with hip infection than with knee infection (HR =0.10, p = 0.013) and were associated with a higher number ofprior revisions (HR = 2.83, p = 0.026) (Table VII).

Discussion

With the rates of total knee and hip arthroplasties performedin the United States expected to increase by 673% and

174%, respectively, from 2005 to 203020, strategies to avoid limb-threatening outcomes and high mortality rates associated withperiprosthetic joint infection are needed. In the current study, weexamined how chronic suppressive antibiotics affect infection-free prosthetic survival rates after surgical intervention for peri-prosthetic joint infection. The five-year infection-free survivalrate in the suppression group was 68.5% compared with 41.1%in the non-suppression group (p = 0.008). The increased survivalrate in the suppression group is consistent with the findings inanother study, which showed a three-year success rate of 78%after treatment of 112 periprosthetic joint infections with de-bridement, antibiotics, and implant retention21. Other studiesdocumenting the management of periprosthetic joint infectionwith antibiotics and prosthesis retention have demonstratedboth positive22,23 and negative24 outcomes; however, subsequentchronic suppression with oral antibiotics was not consistentlyused.

Stratification by the type of surgery and infecting organismshowed that the patients who benefited the most from chronicsuppressive antibiotic therapy were those who underwent irri-gation and debridement with polyethylene exchange and thosewith S. aureus infection. The benefit of suppression followingirrigation and debridement with polyethylene exchange has al-ready been documented and is in accordance with findings in thecurrent literature25-27. Persistence of a latent infection is common

Fig. 4

Kaplan-Meier infection-free prosthetic survival curves for subsets with

MRSA (Fig. 4-A), MSSA (Fig. 4-B), and gram-negative (Fig. 4-C) infection.

Theblue line represents the suppression group, and the red line represents

the non-suppression group; the shaded areas surrounding the lines rep-

resent the 95% CI. Suppressive antibiotics increased the five-year

infection-free prosthetic survival rate for patients withMRSA infection, with

a survival rate of 50.8% (95% CI = 22.2% to 78.9%) in the suppression

group and 28.2% (95% CI = 16.5% to 43.8%) in the non-suppression group

(p = 0.05). There was no difference in the infection-free survival rate

between the suppression group with MSSA infection (63.6% [95% CI =

45.1% to 78.8%]) and the non-suppression group with MSSA infection

(48.1% [95% CI = 34.4% to 62.1%]; p = 0.09). The suppression-group

patients with gram-negative infection had an increased infection-free

survival rate (74.7% [95% CI = 36.7% to 94.1%]) compared with the

non-suppression group with gram-negative infection (20.3% [95% CI =

10.6% to 39.2%]; p = 0.04).

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in patients with retained implants and thus antibiotic sup-pression seems to be a reasonable alternative that avoids theneed for a more invasive two-stage revision. Antibiotic sup-pression following two-stage procedures did not seem to affectprosthetic survival. The current study also showed that, amongthe patients who had S. aureus infection, those who underwentpostoperative suppression had a higher infection-free survivalrate than those who did not receive postoperative suppression.

This conflicts with the findings in the study by Brandt et al.28, inwhich suppression did not influence the outcome of surgicaltreatment of periprosthetic joint infections caused by S. aureus.Possible explanations for this discrepancy are the newer, moreefficacious antibiotic regimens used in the present study, thelonger course of intravenous antibiotics postoperatively (sixweeks versus four weeks in the study by Brandt et al.), anddifferences in the end points that were used. Furthermore, ithas been suggested that S. aureus survives in the intracellularenvironment29, which may account for its higher recurrencerate and thus the need for a long-term oral antibiotic regimen.Finally, chronic antibiotic therapy did not seem to influenceinfection-free survival after revisions for non-S. aureus infec-tions. This was probably due to the greater success attainedwith the surgery and by the increased susceptibility of thesepathogens to intravenous agents used in the first six weeks aftersurgery. Numerous studies have shown the efficacy of chronicsuppression even of non-S. aureus infections25-27, but the ab-sence of a control group in those studies precludes any definiteconclusions from being reached.

TABLE VIII Findings in Previous Studies of Chronic Antibiotic Suppression

Study No.

Mean Durationof Follow-up

(mo)

Mean Durationof AntibioticSuppression(Range) (mo)

Previous SurgicalTreatment Failure Criteria

No. (%) ofSuccessful

Cases

Johnson andBannister30

(1986)

25 knees 15.6 15.6 (1.2-59) Excision of sinus tract,debridement, exchangearthroplasty

Persistentdischarge,joint pain

2 (8%)

Goulet et al.27

(1988)19 hips 49.2 45 (2-120) Incision and drainage

(11), no prior surgery (8)Removal orrevision ofprosthesis,increasingsymptoms ofinfection

9 (47%)

Tsukayamaet al.31

(1991)

8 knees,5 hips

37.6 24.5 (6-48) Surgical debridement Prosthesisremoval forrecurrentinfection

3 (23%)

Segretiet al.25

(1998)

12 knees,6 hips

60 48.9 (4-103) Surgical debridement Persistence ofsymptoms ofinfection (pain,drainage, etc.)

15 (83%)

Rao et al.26

(2003)19 knees,15 hips,2 elbows

61.5 52.6 (6-128) Surgical debridement Developmentof progressivepain, looseningof implant, ordrainage

31 (86%)

Current study 71 knees,21 hips

69.6 63.47 (6-165) Irrigation and debridementwith polyethyleneexchange (54), 2-stagerevision (38)

Additionalsurgery dueto infection,persistentdrainage orjoint pain,death within1 yr

60 (65%)

TABLE VII Penalized Regression Model Estimates of FactorsAssociated with Treatment Failure

Variable HR 95% CI P Value

No. of previous revisions* 2.83 1.14-7.03 0.026

BMI† 1.45 0.68-3.10 0.33

Hip infection 0.10 0.02-0.61 0.013

*Effect for a three-unit change. †Effect for a 12.7-unit change.

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The multivariate models constructed for our study con-firmed the overall benefit of chronic antibiotic therapy. However,this analysis was not able to determine the subset from whichthis benefit was mostly derived, probably because of the limitednumber of events in each subset and overfitting of the datawithin the model.

The 34.8% failure rate for the ninety-two patients who re-ceived chronic antibiotic therapy for a minimum of six months washigher than the rates in the most recently published studies25,26.Segreti et al.25 reviewed the cases of eighteen patients who hadundergone surgical debridement and six to eight weeks of intra-venous antibiotics followed by prolonged antibiotic suppression.At five years, only three had persistent symptoms of infection. Raoet al.26 prospectively examined thirty-six patients who had under-gone the same protocol of surgical debridement and four to sixweeks of intravenous antibiotics prior to antibiotic suppression.The failure rate was 13.9% (five of the thirty-six patients) after4.4 years of follow-up. Possible explanations for the higher failurerates observed in the present study include the higher prevalenceof invasive pathogens (47.8% of the infections were caused byS. aureus compared with 38.9% in the other studies25,26) and theinclusion of deaths within the first year after treatment as failures.Older studies on chronic antibiotic suppression27,30,31 showed higherfailure rates, probably as a result of less efficient antibiotic regi-mens (Table VIII). In our study, patients for whom suppressiveantibiotic treatment failed had had more prior joint revisions.The association of a higher number of previous revisions withincreased failure rates is in accordance with the findings in otherstudies32,33. We also found that patients with knee periprostheticjoint infection had a higher rate of failure than those with hipinfection. In a review of 9245 cases, Pulido et al.6 reported anincreased prevalence of periprosthetic joint infection after totalknee arthroplasty than after total hip arthroplasty. This doesnot explain why knees have an inferior response to treatment ofperiprosthetic joint infection, but it provides some evidence of anincreased susceptibility to periprosthetic joint infection in knees.

Our study was limited by its sample size. This is a commonlimitation of studies of chronic antibiotic suppression for peri-prosthetic joint infection because it is a last-resort treatment foran infrequent complication of joint arthroplasty. The smallsample size compromised the ability of the multivariate analyses

stratified by the infecting organism, affected joint, and type ofsurgery to provide results similar to those in the survivorshipanalysis. In addition, sampling bias was an inherent limitation ofour study when the suppression group was compared with thenon-suppression group. In an effort to overcome this bias, pro-pensity score matching with a 3:1 matching ratio was done foreight variables. Also, the retrospective nature of the study pre-cluded the use of standardized surgical techniques and antibioticregimens. Finally, the six subset cohorts had lower-quality pro-pensity score matching than the cohort as a whole. This wasthe case because the matching was designed to produce goodmatches for all subjects rather than within subsets.

In summary, chronic suppression with oral antibioticsresulted in superior infection-free survival rates after surgicaltreatment for periprosthetic joint infection compared with thoseobserved without suppression. Patients who underwent irriga-tion and debridement with polyethylene exchange and thosewith S. aureus infection showed the greatest benefit. Knee infec-tion and a greater number of prior revisions were identified asvariables associated with treatment failure. n

Marcelo B.P. Siqueira, MDAnas Saleh, MDAlison K. Klika, MSColin O’Rourke, MSSteven Schmitt, MDCarlos A. Higuera, MDWael K. Barsoum, MDDepartments of Orthopaedic Surgery(M.B.P.S., A.S., A.K.K., C.A.H., and W.K.B.),Quantitative Health Sciences (C.O’R.),and Infectious Diseases (S.S.),Cleveland Clinic Foundation,Cleveland, OH 44195.E-mail address for M.B.P. Siqueira: [email protected] address for A. Saleh: [email protected] address for A.K. Klika: [email protected] address for C. O’Rourke: [email protected] address for S. Schmitt: [email protected] address for C.A. Higuera: [email protected] address for W.K. Barsoum: [email protected]

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